Dose Intensity for Breast Cancer

Dose Intensity for Breast Cancer

Drs. Armstrong and Davidson
have nicely reviewed the use
of dose-intensive chemotherapy in the treatment of metastatic and high-risk
early-stage breast cancer, and we agree with the basic premise of the articlethat
there are no conclusive data to support the routine use of doses beyond the
standard range outside of a study setting. Bonadonna et al in 1981 demonstrated
that inferior dosing of CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar],
methotrexate, fluorouracil [5-FU]) in node-positive breast cancer was equivalent
to not receiving chemotherapy at all.[1] Extrapolating from this information and
from data from other supportive studies, a number of prospective trials of more
dose-intensive regimens were undertaken in the next 2 decades.

Dose Threshold

Many trials have demonstrated that increased dose intensity
could potentially result in better response rates and sometimes in prolongation
of median time to progression but not in improved survival. Dose thresholds have
been established for many active agentsdoxorubicin (60 mg/m2);
cyclophosphamide (600 mg/m2), paclitaxel (175 mg/m2)as has the fact that
adequate dosing is essential (dose threshold). Escalation beyond standard dosing
remains a question for study with no convincing evidence of efficacy and some
data demonstrating harm in terms of second malignancies, especially in the case
of leukemogenesis with high-dose alkylating agents.

An interesting hypothesis currently being investigated in
prospective trials is that of dose density. This strategy calls for decreasing
time between treatments (ie, the time available for tumor regrowth is reduced)
by using sequential administration of single agents in an intensive fashion
rather than in combination. This concept has a theoretical appeal that it is
hoped will translate into a survival benefit in prospective trials currently
underway.

Metastatic Breast Cancer

There are now five reported prospective randomized trials of
high-dose chemotherapy and stem cell support in advanced breast cancer. We agree
with the authors that the 1995 Bezwoda trial[2] must be discarded because of
uncertain validity, especially in light of this investigator’s admittedly
fraudulent data on the role of this therapy in high-risk breast cancer,
presented in abstract form at the plenary session of ASCO 1999.[3] We are thus
left with four randomized trials in the metastatic setting on which to comment.

The French PEGASE 4 trial although small (61 patients
randomized), did show a trend toward improvement of median overall survival for
the high-dose arm, but that trend was not statistically significant.[4] The
results suggested, however, that this therapeutic approach holds promise. The
Philadelphia Intergroup study, did not show any incremental benefit for
high-dose chemotherapy in 3-year overall, or relapse-free survival.[5] Criticism
regarding the number of eligible patients actually randomized (199 patients in
the analysis) is unwarranted. This was a study of two postremission approaches.
Only 310 patients responded to induction therapy and thus were eligible for
randomization; the majority were thus randomized.

We are unsure of how to interpret the prolonged median survival
of the group receiving high-dose chemotherapy at second recurrence (3.2 years)
rather than at first complete remission (2.3 years) in the Duke Crossover study
(98 patients).[6] The only patients randomized were those in complete remission,
which represented approximately 25% of the original 400 patients entered into
the study. We await final analysis and publication of the complete manuscript to
interpret these data further.

Investigators at Duke also looked at high-dose chemotherapy in
69 patients with breast cancer that had metastasized to a limited number of bone
sites.[7] They again examined the role of delayed vs immediate vs high-dose
chemotherapy after standard chemotherapy. The difference in progression-free
survival (1.0 vs 0.91 years) has been reported as significantly favoring
high-dose chemotherapy, although one could well question the clinical
significance; indeed, median overall survivals were approximately the same (2.01
vs 1.8 years) at 4.9 years median follow-up.

Thus, despite more than 10 years of investigation with over
5,000 patients treated and a collective randomized trial experience in over 400
patients, there is no definitive evidence of the therapeutic efficacy of
high-dose chemotherapy in metastatic breast cancer. A number of other randomized
trials in metastatic breast cancer remain to be reported. We believe that until
proof of principle is demonstrated in the adjuvant high-risk breast cancer
setting, where treatment of micrometastatic disease is the goal, use of this
modality in metastatic breast cancer should be limited to innovative clinical
investigations.

High-Risk Breast Cancer

Turning to early-stage breast cancer and high-dose chemotherapy,
there are six randomized published trials, one of which is the strongly positive
but discredited South African study mentioned earlier. A Dutch pilot trial
examined the role of high-dose chemotherapy (with cyclophosphamide, thiotepa
[Thioplex], and carboplatin [Paraplatin]) in 97 patients with a positive
infraclavicular lymph node biopsy who had responded to initial treatment with
preoperative FEC (fluorouracil, epirubicin [Ellence], cyclophosphamide).[8] At a
median follow-up of 49 months there was no difference in progression-free or
overall survival between the two arms.

The same group has now enrolled 885 patients with four or more
positive axillary lymph nodes and examined the same high-dose chemotherapy
regimen used in the pilot study in place of a fifth cycle of FEC.[9] A planned
subgroup analysis of the first 284 patients showed a benefit in 3-year overall
and relapse-free survival. The results are promising, but the final results are
not expected until 2002. Meanwhile, enthusiasm must be tempered by the other
studies reported to date.

An M. D. Anderson trial in 78 patients with 10 or more positive
axillary nodes showed no benefit for the high-dose arm at a median follow-up of
6.5 years.[10] A 525-patient trial
by the Scandinavian Breast Cancer Study Group reported no difference
in relapse-free or overall survival at
a 2-year median follow-up.[11] A
CALGB Intergroup trial in 874 women with 10 or more involved lymph nodes found
similar event-free and overall survival data at a median follow-up of 37 months
and, so far, does not favor high-dose therapy, although a trend toward reduced
relapse-free survival is evident.[12]

Comments and Recommendations

What can we conclude? Unfortunately, most patients with
metastatic breast cancer still relapse and die within 3 years, and better
therapeutic interventions are needed. High-dose chemotherapy and stem cell
rescue does allow for increased dose density, intensity, and response. The
morbidity, mortality, and cost of high-dose chemotherapy with stem cell rescue
has decreased substantially over the past decade, and quality of life does not
decline substantially after transplant. These observations support further study
of this approach.

However, the incorporation of one cycle of high-dose
chemotherapy and stem cell rescue into the treatment of metastatic breast cancer
has so far been associated with no difference in overall or relapse-free
survival. Follow-up of these studies is adequate given the short natural history
of metastatic breast cancer, and these results are unlikely to change with
longer observation. The design of the reported studies reflects current practice
but such treatment may be suboptimal; promising designs such as double/tandem
transplants, stem cell purging, immunotherapy, and so forth are worthy of active
investigation.

The incorporation of high-dose chemotherapy with stem cell
rescue into the treatment of high-risk breast cancer, however, has been much
more successful. All studies show a greater than 60% to 70% 3-year relapse-free
survival, and this is as good as the results obtained with any other treatment
for high-risk breast cancer. The follow-up periods for these studies are not yet
long enough to determine benefit in light of the long natural history of
high-risk breast cancer. We also need to await mature results of other ongoing
trials in high-risk breast cancer for final answers.

We still believe that high-dose therapy and stem cell rescue
will ultimately be shown to improve outcome in breast cancer. We agree, however,
that up to this point this has not been demonstrated, and use of this modality
should be limited to well-designed clinical trials. These studies should be
supported by physicians, patients, and third-party payers. The past history of
inadequate support for these trials has led to delayed information, to the
detriment of us all. That said, we hope and believe that the next generation of
therapeutic interventions will be even more effective and make the entire matter
of high-dose chemotherapy and stem cell transplant for breast cancer moot.